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Aim To explore whether left atrial (LA) strain with speckle tracking echocardiography (STE) can contribute to prognostication in patients with congenital aortic stenosis (CAS). Methods and results In this prospective study, consecutive outpatients with stable CAS and healthy adults were enrolled between 2011 and 2015. Left atrial function was analysed with STE using Tomtec software. Associations between LA strain (LAS) measurements and primary composite outcome (any adverse cardiovascular event, hospitalization, or re-intervention) and secondary outcome (re-interventions) were assessed with Cox regression analysis. In total, 98 patients with CAS (mean age: 35.0+11.9 year, female: 59.2%) and 121 controls (age: 43.9+13.8 year, female: 55.4%) were included. The majority of patients were in NYHA class I: 97 (99%) at baseline. At baseline, LA conduit strain (LAS-cd) and strain rate (LASR-cd) were significantly lower in patients than in controls when corrected for age and sex (-18.1+8.7 vs. -23.5+9.9%, P= 0.001 and -0.73+0.31 vs. -1.02+0.43/s, P,0.001). During a median follow-up of 6.4 years (5.7-7.1), the primary composite outcome occurred in 48 (39.6%) patients. Kaplan-Meier analysis showed that decreased LAS-cd (,21%) was associated with a higher occurrence of the primary outcome (log-rank: P=0.008). Depressed LAS-cd and LASR-cd were both associated with the primary composite outcome [univariable hazard ratio (HR)=0.64(0.46-0.88), P=0.005 and HR=0.68(0.55-0.83), P,0.001, respectively]; adjusted HR (for LAS-cd and LASR-cd, respectively): 0.31(0.09-1.04), P=0.06 and 0.49(0.26-0.89), P=0.02. Conclusion Impairment in LA conduit function assessed with STE carries prognostic value in patients with CAS and can be implemented in clinical management.

Objectives: Right ventricular (RV) failure post left ventricular assist device (LVAD) implantation is associated with increased morbidity and mortality. A novel RV multi-plane imaging method using two-dimensional echocardiography and electronic plane rotation (MPE) was used to quantify RV function prior to LVAD implantation and to identify potential added value in this patient population. Methods: In twenty-five end-stage heart failure patients (age 58.9 ± 6.8 years, 76% male), systolic function of four different RV walls (lateral, anterior, inferior and inferior coronal) were evaluated from one focussed apical view using MPE. Results: Feasibility of tricuspid annular plane systolic excursion (TAPSE) and tricuspid annular peak systolic velocity (RV-S') measurements were high (84–100%), with lower TAPSE values measured in the inferior (14.2 ± 4.6 mm) and inferior coronal (12.3 ± 5.0 mm) walls compared to the lateral (16.3 ± 4.5 mm) and anterior walls (16.0 ± 4.5 mm). RV wall longitudinal strain (RV-LS) measurement was most feasible in the lateral wall (80%; mean: –12.1 ± 4.2%). TAPSE and RV-LS values were significantly reduced in patients compared to matched healthy individuals (p = <0.001). Seven (28%) patients who developed moderate to severe RV failure (RVF) early post-implant (≤30 days) had lower pre-implant values across all multi-plane parameters compared to those without significant post-implant RVF, notably four-wall averaged TAPSE (11.1 ± 3.4 mm vs 15.9 ± 4.0 mm; p = 0.02). Conclusion: 2D MPE was highly feasible for RV wall quantification pre-LVAD surgery, detecting differences in regional wall function. This novel method comprehensively quantifies RV wall function and could complement current pre-LVAD screening protocols.

The prognosis of pulmonary arterial hypertension (PAH) remains dismal. Over the years, multiple therapeutic advances have been introduced. This study evaluates the evolution of PAH survival over the past 15 years. We included 293 consecutive adult patients diagnosed with PAH between 2005 and 2019 (median age: 61.8 years, 70.3% female). Patients were divided into three cohorts based on the time of diagnosis: 2005–2009, 2010–2014, and 2015–2019 (2005–2009: n = 56; 2010–2014: n = 111; 2015–2019: n = 126). Transplant-free survival was measured from the date of right heart catheterization until patients reached the composite endpoint of lung transplant or death. Multivariable cox-pulmonary hypertension regression was used to study the effect of the time of diagnosis. The final cox model was fitted in both younger and older patients to evaluate the difference between these groups. During a median follow-up time of 4.1 (interquartile range: 2.2–7.3) years, 9 patients underwent lung transplantation and 151 patients died. The median overall transplant-free survival was 6.2 (5.5–8.0) years. Patients older than 56 years at baseline who were diagnosed in 2005–2009 showed better survival compared to patients diagnosed in 2010–2014 and 2015–2019 with an adjusted hazard ratio of, respectively, 2.12 (1.11–4.03) and 2.83 (1.41–5.69). Patients younger than 56 years showed neither an improved nor deteriorated survival over time. In conclusion, survival in patients with PAH did not improve over time, despite more available therapeutic options. This might be partly due to the changed demographic characteristics of the PAH patients and a still important diagnostic delay.

Background: Multiple biomarkers have been investigated in the risk stratification of patients with pulmonary arterial hypertension (PAH). This systematic review and meta-analysis is the first to investigate the prognostic value of (NT-pro)BNP in patients with PAH. Methods: A systematic literature search was performed using MEDLINE, Embase, Web of Science, the Cochrane Library and Google scholar to identify studies on the prognostic value of baseline (NT-pro)BNP levels in PAH. Studies reporting hazard ratios (HR) for the endpoints mortality or lung transplant were included. A random effects meta-analysis was performed to calculate the pooled HR of (NT-pro)BNP levels at the time of diagnosis. To account for different transformations applied to (NT-pro)BNP, the HR was calculated for a 2-fold difference of the weighted mean (NT-pro)BNP level of 247 pmol/L, for studies reporting a HR based on a continuous (NT-pro)BNP measurement. Results: Sixteen studies were included, representing 6999 patients (mean age 45.2-65.0 years, 97.3% PAH). Overall, 1460 patients reached the endpoint during a mean follow-up period between 1 and 10 years. Nine studies reported HRs based on cut-off values. The risk of mortality or lung transplant was increased for both elevated NT-proBNP and BNP with a pooled HR based on unadjusted HRs of 2.75 (95%-CI: 1.86-4.07) and 3.87 (95% CI 2.69-5.57) respectively. Six studies reported HRs for (NT-pro)BNP on a continues scale. A 2-fold difference of the weighted mean NT-proBNP resulted in an increased risk of mortality or lung transplant with a pooled HR of 1.17 (95%-CI: 1.03-1.32). Conclusions: Increased levels of (NT-pro)BNP are associated with a significantly increased risk of mortality or lung transplant in PAH patients.

BACKGROUND: Genetic testing of relatives of hypertrophic cardiomyopathy (HCM) patients has led to a large group of genotype-positive, phenotype-negative (G+/Ph-) subjects. Prediction of progression to overt HCM in these subjects is challenging. While left atrial (LA) strain is reduced in HCM patients it is currently unknown whether this parameter can be used to predict HCM phenotype progression.METHODS: This study includes 91 G+/Ph- subjects and 115 controls. Standard echocardiographic parameters as well as left ventricular global longitudinal strain (LV GLS) and LA reservoir strain (LASr) were assessed for each patient. Logistic and Cox proportional hazard regression analyses were used to investigate predictors of G+/Ph- status and HCM during follow-up.RESULTS: Independent predictors of G+ status included pathological Q waves (OR 1.60 [1.15-2.23], p < .01), maximal wall thickness (MWT: OR 1.10 [1.07-1.14], p < .001), mitral inflow E wave (OR 1.06 [1.02-1.10, p = .001), A wave (OR 1.06 [1.03-1.10], p < .001), LV GLS (OR .96 [.94-.98], p < .001), and LASr (OR .99 [.97-.99], p = .03). In univariable Cox regression analysis, male sex (HR 2.78 [1.06-7.29], p = .04), MWT (HR 1.72 [1.14-2.57], p = .009) and posterior wall thickness (HR 1.65 [1.17-2.30], p = .004) predicted HCM during a median follow-up of 5.9 [3.2-8.6] years, whereas LASr did not (HR .95 [.89-1.02], p = .14). There were no significant predictors of HCM after multivariable adjustment.CONCLUSION: LASr is significantly impaired in G+/Ph- subjects and is an independent predictor of G+/Ph- status, but did not predict HCM development during follow-up.

High-frame-rate (HFR) echo-particle image velocimetry (echoPIV) is a promising tool for measuring intracardiac blood flow dynamics. In this study, we investigate the optimal ultrasound contrast agent (UCA: SonoVue) infusion rate and acoustic output to use for HFR echoPIV (PRF = 4900 Hz) in the left ventricle (LV) of patients. Three infusion rates (0.3, 0.6, and 1.2 ml/min) and five acoustic output amplitudes (by varying transmit voltage: 5, 10, 15, 20, and 30 V - corresponding to mechanical indices of 0.01, 0.02, 0.03, 0.04, and 0.06 at 60-mm depth) were tested in 20 patients admitted for symptoms of heart failure. We assess the accuracy of HFR echoPIV against pulsed-wave Doppler acquisitions obtained for mitral inflow and aortic outflow. In terms of image quality, the 1.2-ml/min infusion rate provided the highest contrast-to-background ratio (CBR) (3-dB improvement over 0.3 ml/min). The highest acoustic output tested resulted in the lowest CBR. Increased acoustic output also resulted in increased microbubble disruption. For the echoPIV results, the 1.2-ml/min infusion rate provided the best vector quality and accuracy; mid-range acoustic outputs (corresponding to 15-20-V transmit voltages) provided the best agreement with the pulsed-wave Doppler. Overall, the highest infusion rate (1.2 ml/min) and mid-range acoustic output amplitudes provided the best image quality and echoPIV results., ImPhys/Medical Imaging

AIMS: Patients with adult congenital heart disease (ACHD) are a potentially vulnerable patient cohort in case of COVID-19. Some cardiac defects may be associated with a poor COVID-19 outcome. Risk estimation in ACHD is currently based on expert opinion. The aim of this study was to collect clinical outcome data and to identify risk factors for a complicated course of COVID-19 in patients with ACHD. METHODS: Twenty-five ACHD centres in nine European countries participated in the study. Consecutive patients with ACHD diagnosed with COVID-19 presenting to one of the participating centres between 27 March and 6 June 2020 were included. A complicated disease course was defined as hospitalisation for COVID-19 requiring non-invasive or invasive ventilation and/or inotropic support, or a fatal outcome. RESULTS: Of 105 patients with a mean age of 38±13 years (58% women), 13 had a complicated disease course, of whom 5 died. In univariable analysis, age (OR 1.3, 95% CI 1.1 to 1.7, per 5 years), ≥2 comorbidities (OR 7.1, 95% CI 2.1 to 24.5), body mass index of >25 kg/m2 (OR 7.2, 95% CI 1.9 to 28.3) and cyanotic heart disease (OR 13.2, 95% CI 2.5 to 68.4) were associated with a complicated disease course. In a multivariable logistic regression model, cyanotic heart disease was the most important predictor (OR 60.0, 95% CI 7.6 to 474.0). CONCLUSIONS: Among patients with ACHD, general risk factors (age, obesity and multiple comorbidities) are associated with an increased risk of complicated COVID-19 course. Congenital cardiac defects at particularly high risk were cyanotic lesions, including unrepaired cyanotic defects or Eisenmenger syndrome.

Introduction Autoreactivity against pulmonary vascular structures is thought to be involved in idiopathic pulmonary arterial hypertension (IPAH), but the underlying mechanisms remain poorly understood. We hypothesised that aberrant B-cell activation contributes to IPAH aetiology. Methods Mice with enhanced B-cell activation due to B-cell-specific overexpression of the B-cell receptor (BCR) signalling molecule Bruton's tyrosine kinase (BTK) were subjected to lung injury and examined for several pulmonary hypertension (PH) indices. Peripheral blood lymphocytes from patients with IPAH (n=13), connective tissue disease-associated PAH (CTD-PAH, n=9), congenital heart disease PAH (n=7), interstitial lung disease associated PH (n=17) and healthy controls (n=19) were characterised by 14-colour flow cytometry. Results Following pulmonary injury, BTK-overexpressing mice showed prolonged activation of B cells and CXCR5 + follicular T-helper (Tfh) cells, as well as features of PH development. Patients with CTD-PAH and CHD-PAH displayed reduced proportions of circulating non-switched-memory B cells (p=0.03, p=0.02, respectively). Interestingly, we observed increased BTK protein expression in naive (p=0.007) and memory B-cell subsets of patients with IPAH and CTD-PAH. BTK was particularly high in patients with IPAH with circulating autoantibodies (p=0.045). IPAH patients had low frequencies of circulating CXCR5 + Tfh cells (p=0.005). Hereby, the increased BTK protein expression in B cells was associated with high proportions of Tfh17 (p=0.018) and Tfh17.1 (p=0.007) cells within the circulating Tfh population. Conclusions Our study shows that pulmonary injury in combination with enhanced B-cell activation is sufficient to induce PH symptoms in mice. In parallel, immune homeostasis in patients with IPAH is compromised, as evidenced by increased BCR signalling and cTfh17 polarisation, indicating that adaptive immune activation contributes to IPAH disease induction or progression.

Aim: This study aimed to describe the systolic left ventricular global longitudinal strain (LvGLS) and left ventricular peak early diastolic strain rate (Sre) in adult women with Turner syndrome (TS) and to determine its rela-tionship with exercise capacity and clinical parameters. Methods: In this cross-sectional cohort study, consecutively included adult TS women underwent an electrocardiogram, transthoracic echocardiogram (TTE) and cardiopulmonary exercise test (CPET) on the same day. LvGLS and Sre were measured using 2D speckle tracking analysis (STE) and compared with age-matched healthy female controls. Results: Ninety-four adult women (age 36 ± 13 years) with TS and 32 healthy age-matched female controls were included. Women with TS had a significantly impaired/reduced systolic LvGLS (–17.82 ± 2.98% vs. –21.80 ± 1.85%, p <0.001)and Sre (0.98 ± 0.32 s-1 vs. 1.27 ± 0.19 s-1, p > 0.001), compared to healthy female controls. Furthermore, TS women had reduced diastolic function as measured by conventional echocardiographic parameters: A higher A-wave (p < 0.001), lower E/A-ratio (p = 0.001), longer deceleration time (p = 0.006), and a higher E/E’-ratio (p <0.001).WomenwithTSalsohadasignificantly reduced maximal workload (p = 0.033), reduced oxygen uptake (p < 0.001) and a reduced maximal heart rate (p < 0.001) during exercise. Multivariable linear regression analysis revealed that Age, karyotype and QT-duration were significantly associated with Sre, but not with LvGLS, in the TS population. Conclusion: Systolic and diastolic strain and exercise capacity were significantly reduced in TS women compared to healthy women. No correlation between strain itself and exercise capacity could be demonstrated, but correlations with conventional TTE parameters and baseline characteristics were found.

[Aims] Patients with adult congenital heart disease (ACHD) are a potentially vulnerable patient cohort in case of COVID-19. Some cardiac defects may be associated with a poor COVID-19 outcome. Risk estimation in ACHD is currently based on expert opinion. The aim of this study was to collect clinical outcome data and to identify risk factors for a complicated course of COVID-19 in patients with ACHD., [Methods] Twenty-five ACHD centres in nine European countries participated in the study. Consecutive patients with ACHD diagnosed with COVID-19 presenting to one of the participating centres between 27 March and 6 June 2020 were included. A complicated disease course was defined as hospitalisation for COVID-19 requiring non-invasive or invasive ventilation and/or inotropic support, or a fatal outcome., [Results] Of 105 patients with a mean age of 38±13 years (58% women), 13 had a complicated disease course, of whom 5 died. In univariable analysis, age (OR 1.3, 95% CI 1.1 to 1.7, per 5 years), ≥2 comorbidities (OR 7.1, 95% CI 2.1 to 24.5), body mass index of >25 kg/m2 (OR 7.2, 95% CI 1.9 to 28.3) and cyanotic heart disease (OR 13.2, 95% CI 2.5 to 68.4) were associated with a complicated disease course. In a multivariable logistic regression model, cyanotic heart disease was the most important predictor (OR 60.0, 95% CI 7.6 to 474.0)., [Conclusions] Among patients with ACHD, general risk factors (age, obesity and multiple comorbidities) are associated with an increased risk of complicated COVID-19 course. Congenital cardiac defects at particularly high risk were cyanotic lesions, including unrepaired cyanotic defects or Eisenmenger syndrome.

Background: Right ventricular (RV) function is recognized as an important prognostic factor in adult congenital heart disease (ACHD). The accuracy of established parameters including tricuspid annular plane systolic excursion (TAPSE), RV fractional area change (RVFAC) and tissue Doppler imaging (TDI S′) is limited as only a small RV region is reflected. We previously introduced a novel four-view approach with different RV walls visualized from one apical view using electronic plane rotation, also known as iRotate. Aim: To evaluate the entire RV function using electronic plane rotation echocardiography within the spectrum of ACHD compared with healthy subjects. Methods and results: One hundred and forty-two ACHD patients were recruited from the outpatient clinic and 89 healthy subjects. All subjects underwent a transthoracic echocardiogram with evaluation of TAPSE, TDI S′ and peak systolic longitudinal RV strain (RV-LS) from all RV walls using the four-view electronic plane rotation model. With exception of TDI S′ in inferior coronal view, all parameters were lower in ACHD vs healthy subjects (p < 0.001). Within the ACHD patients, RV strain was lower in anterior (−15.9 ± 4.9) and inferior coronal view (−15.1 ± 4.5) versus lateral (−17.6 ± 5.0) and inferior wall (−17.2 ± 4.7) (p < 0.05). RV-LS values of systemic RV were lower (p < 0.05), but no difference was observed between subpulmonic RV loading conditions. Conclusion: The four-view electronic plane rotation model represents a reproducible, easily applicable and complete RV assessment in daily practice. RV function is significantly decreased in the ACHD group using both regional and global assessment parameters. Complete RV strain analysis reveals regional differences.

BACKGROUND: The long-term burden of cardiovascular disease after repair of coarctation of the aorta (CoA) has not been eluci-dated. We aimed to determine the incidence of and risk factors for cardiovascular events in adult patients with repaired CoA. Additionally, mortality rates were compared between adults with repaired CoA and the general population. METHODS AND RESULTS: Using the Dutch Congenital Corvitia (CONCOR) registry, patients aged ≥16 years with previous surgical or transcatheter CoA repair from 5 tertiary referral centers were included. Cardiovascular events were recorded, comprising coronary artery disease, stroke/transient ischemic attack, aortic complications, arrhythmias, heart failure hospitalizations, en-docarditis, and cardiovascular death. In total, 920 patients (median age, 24 years [range 16–74 years]) were included. After a mean follow-up of 9.3±5.1 years, 191 patients (21%) experienced at least 1 cardiovascular event. A total of 270 cardiovascular events occurred, of which aortic complications and arrhythmias were most frequent. Older age at initial CoA repair (hazard ratio [HR], 1.017; 95% CI, 1.000–1.033 [P=0.048]) and elevated left ventricular mass index (HR, 1.009; 95% CI, 1.005–1.013 [P<0.001]) were independently associated with an increased risk of cardiovascular events. The mortality rate was 3.3 times higher than expected based on an age-and sex-matched cohort from the Dutch general population (standardized mortality ratio, 3.3; 95% CI, 2.3– 4.4 [P<0.001]). CONCLUSIONS: This large, prospective cohort of adults with repaired CoA showed a high burden of cardiovascular events, particularly aortic complications and arrhythmias, during long-term follow-up. Older age at initial CoA repair and elevated left ventricular mass index were independent risk factors for the occurrence of cardiovascular events. Mortality was 3.3-fold higher compared with the general population. These results advocate stringent follow-up after CoA repair and

Purpose: Bicuspid aortic valve (BAV) is a complex malformation affecting not merely the aortic valve. However, little is known regarding the dynamic physiology of the aortic annulus in these patients and whether it is similar to tricuspid aortic valves (TAV). Determining the BAV annular plane is more challenging than for TAV. Our aim was to present a standardized methodology to determine BAV annulus and investigate its changes in shape and dimensions during the cardiac cycle. Methods: BAV patients were prospectively included and underwent an ECG-gated cardiac CTA. The annulus plane was manually identified on reconstructions at 5% intervals of the cardiac cycle with a new standardized method for different BAV types. Based on semi-automatically defined contours, maximum and minimum diameter, area, area-derived diameter, perimeter, asymmetry ratio (AR), and relative area were calculated. Differences of dynamic annular parameters were assessed also per BAV type. Results: Of the 55 patients included (38.4 ± 13.3 years; 58% males), 38 had BAV Sievers type 1, 10 type 0, and 7 type 2. The minimum diameter, perimeter, area, and area-derived diameter were significantly higher in systole than in diastole with a relative change of 13.7%, 4.8%, 13.7%, and 7.2% respectively (all p < 0.001). The AR was ≥ 1.1 in all phases, indicating an elliptic shape, with more pronounced flattening in diastole (p < 0.001). Different BAV types showed comparable dynamic changes. Conclusions: BAV annulus undergo significant changes in shape during the cardiac cycle with a wider area in systole and a more elliptic conformation in diastole regardless of valve type. Key Points: • A refined method for the identification of the annulus plane on CT scans of patients with bicuspid aortic valves, tailored for the specific anatomy of each valve type, is proposed. • The annulus of patients with bicuspid aortic valves undergoes significant changes during the cardiac cycle with a wider area and more c

High-frame-rate (HFR) echo-particle image velocimetry (echoPIV) is a promising tool for measuring intracardiac blood flow dynamics. In this study, we investigate the optimal ultrasound contrast agent (UCA: SonoVue) infusion rate and acoustic output to use for HFR echoPIV (PRF = 4900 Hz) in the left ventricle (LV) of patients. Three infusion rates (0.3, 0.6, and 1.2 ml/min) and five acoustic output amplitudes (by varying transmit voltage: 5, 10, 15, 20, and 30 V - corresponding to mechanical indices of 0.01, 0.02, 0.03, 0.04, and 0.06 at 60-mm depth) were tested in 20 patients admitted for symptoms of heart failure. We assess the accuracy of HFR echoPIV against pulsed-wave Doppler acquisitions obtained for mitral inflow and aortic outflow. In terms of image quality, the 1.2-ml/min infusion rate provided the highest contrast-to-background ratio (CBR) (3-dB improvement over 0.3 ml/min). The highest acoustic output tested resulted in the lowest CBR. Increased acoustic output also resulted in increased microbubble disruption. For the echoPIV results, the 1.2-ml/min infusion rate provided the best vector quality and accuracy; mid-range acoustic outputs (corresponding to 15-20-V transmit voltages) provided the best agreement with the pulsed-wave Doppler. Overall, the highest infusion rate (1.2 ml/min) and mid-range acoustic output amplitudes provided the best image quality and echoPIV results.